Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5

Abstract

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

Distal Arthrogryposis with Impaired Proprioception and Touch: Description of an Early Phenotype in a Boy with Compound Heterozygosity of PIEZO2 Mutations and Review of the Literature

“…Biallelic loss-of-function mutations in PIEZO2 cause a specific DAIPT phenotype, including severe hypotonia with significant delay of motor milestones, transient respiratory distress and feeding problems in early infancy as well as symptoms of severe progressive scoliosis and progressive contracture deformities of the hands and feet (distal arthrogryposis). Comparing the features of recessive and dominant PIEZO2-associated diseases, distal arthrogryposis in the dominant forms is typically congenital, whereas scoliosis is less frequent, reported in only 16 of 61 patients [McMillin et al, 2014]. Respiratory and feeding problems in infancy have not yet been described in dominant PIEZO2-associated diseases, but progressive restrictive lung disease in adults has been observed in DA5.…”

“…DA3 (Gordon syndrome) involves an additional cleft palate or a bifid uvula. Patients with DA5 also manifest various ocular symptoms (e.g., ophthalmoplegia, ptosis, deep-set eyes, blepharophimosis, and retinal abnormalities) and progressive restrictive lung disease [McMillin et al, 2014;Alisch et al, 2017]. However, some features of dominant PIEZO2 -associated diseases overlap.…”

“…Intellectual development is normal also in dominant PIEZO2-associated diseases, with the exception of the most severe and rare form, the Marden-Walker syndrome, which apart from joint contractures and kyphoscoliosis includes many additional anomalies (mask-like face, blepharophimosis, micrognathia, cleft palate, chest deformities, failure to thrive, and renal and cerebral anomalies). However, to date, only a single patient with Marden-Walker syndrome has been confirmed to carry a dominant PIEZO2 mutation [McMillin et al, 2014]. DA3 (Gordon syndrome) involves an additional cleft palate or a bifid uvula.…”

“…The heterozygous carriers (parents and siblings) were healthy. In contrast, the dominant PIEZO2 gain-offunction mutations result in distal arthrogryposis type 3 (DA3 or Gordon syndrome, with cleft palate, OMIM 114300), distal arthrogryposis type 5 (DA5 with eye anomalies, OMIM 108145), or Marden-Walker syndrome (OMIM 248700) [Coste et al, 2013;McMillin et al, 2014]. Here, we report the youngest patient with DAIPT who has been observed to date, revealing a distinct early phenotype with some new features and review the clinical characteristics of the DAIPT patients from the literature.…”

Digitotalar dysmorphism: Molecular elucidation

“…[3] It has also emerged that there is considerable molecular heterogeneity in the DAs and that some conditions regarded as having autonomous syndromic status have identical mutational determinants. [4,5] The prototype DTD family was restudied in 1995 and 2006, and biological specimens were obtained for molecular studies. A causative mutation in the TNNT3 (OMIM #600692) gene has now been identified.…”